About AIP
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
AIP c.811C>T, p.(Arg271Trp)
Classification
Uncertain significance
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
LYFE Sciences is an AI system, and it can make mistakes.
Criteria may be applied incorrectly, sources may be misread, and a
confident-looking classification can still be wrong.
Double-check every criterion and its underlying evidence
before relying on any call.
01The reasoning
How it was classified
The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 2
Benign evidence criteria: 0
Pathogenic criteria applied · 2
PM2Supporting
PM2 · supporting
This variant is rare in population databases. In gnomAD v2.1 the total allele frequency is 4.01706e-06 (1/248938, 0.00040%), and in gnomAD v4.1 the total allele frequency is 3.10087e-06 (5/1612452, 0.00031%), both well below the 0.1% rarity threshold used for PM2 in this generic review.
PP3Supporting
PP3 · supporting
Multiple computational results support a deleterious effect on the protein. REVEL is 0.785 and BayesDel is 0.292581, both favoring a damaging missense effect, while SpliceAI shows no predicted splice impact (max delta score 0.00). Overall, the in silico evidence supports pathogenicity at the protein level.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Uncertain significance
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting, PP3 supporting; combination = 2 supporting, which maps to VUS.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
5 / 1,612,452 alleles
gnomAD v4.1: 5 / 1,612,452 alleles. Recorded AF 3.10087e-06. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 4.01706e-06; MAF= 0.00040%, 1/248938 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 3.26797e-05; MAF= 0.00327%, 1/30600 alleles, homozygotes = 0).
No screenshot for this evidence
Computational predictions
Not recorded
No SpliceAI or REVEL score is recorded in the fields used for this tile.
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. AIP, an aryl hydrocarbon receptor-interacting protein, is infrequently altered in cancer.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
Not assessed
No COSMIC evidence statement is recorded in this case.
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
28 criteria with recorded statuses: 2 met · 4 not met · 15 not assessed · 7 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
The AIP c.811C>T (p.Arg271Trp) variant has been reported in ClinVar as Pathogenic or Likely pathogenic and has also been described in multiple published AIP-associated pituitary adenoma cohorts, including familial isolated pituitary adenoma families and a large kindred with aggressive pituitary tumors.
This variant is rare in population databases, with an allele frequency of 4.01706e-06 in gnomAD v2.1 and 3.10087e-06 in gnomAD v4.1, both well below the 0.1% threshold used for PM2 in this generic review.
Computational evidence supports a deleterious missense effect, with REVEL 0.785 and BayesDel 0.292581, while SpliceAI predicts no meaningful splice effect with a maximum delta score of 0.00.
No criteria match.
Met · 2
PM2 SupportingThis variant is rare in population databases. In gnomAD v2.1 the total allele frequency is 4.01706e-06 (1/248938, 0.00040%), and in gnomAD v4.1 the total allele frequency is 3.10087e-06 (5/1612452, 0.00031%), both well below the 0.1% rarity threshold used for PM2 in this generic review. Details ▾Hide ▴
Rule
Generic ACMG PM2_supporting rarity threshold
Evidence considered
- gnomAD v2.1 AF 4.01706e-06
- gnomAD v4.1 AF 3.10087e-06
Sources
PP3 SupportingMultiple computational results support a deleterious effect on the protein. REVEL is 0.785 and BayesDel is 0.292581, both favoring a damaging missense effect, while SpliceAI shows no predicted splice impact (max delta score 0.00). Overall, the in silico evidence supports pathogenicity at the protein level. Details ▾Hide ▴
Rule
Generic ACMG PP3 computational support
Evidence considered
- REVEL 0.785
- BayesDel 0.292581
- SpliceAI max delta 0.00
Sources
Not met · 4 · evaluated, threshold not reached
PM1 Available evidence does not show that this variant lies in a well-established mutational hotspot or a critical functional domain without benign variation. Cancer Hotspots did not identify a statistically significant hotspot at this residue. Details ▾Hide ▴
Evidence considered
- No hotspot row found
- TPR-domain structural context reviewed without criterion-level hotspot support
Sources
BA1 Population frequency is far below the benign stand-alone threshold. The highest observed gnomAD v4.1 overall allele frequency is 3.10087e-06 (0.00031%), which is well below 1%. Details ▾Hide ▴
BS1 Population frequency is below the benign strong threshold. The highest observed gnomAD v4.1 overall allele frequency is 3.10087e-06 (0.00031%), which is well below 0.3%. Details ▾Hide ▴
BP4 Available computational evidence does not support a benign interpretation. REVEL is 0.785 and BayesDel is 0.292581, both favoring a damaging missense effect; although SpliceAI predicts no splice disruption (max delta score 0.00), the overall in silico evidence does not support BP4. Details ▾Hide ▴
Evidence considered
- REVEL 0.785
- BayesDel 0.292581
- SpliceAI max delta 0.00
Sources
Not assessed · 15 · no assessment recorded
PS1 No evidence was identified showing that this nucleotide change results in the same amino acid substitution as a previously established pathogenic variant through a different DNA change. Details ▾Hide ▴
Evidence considered
- ClinVar variant record reviewed
Still missing
- No same-amino-acid alternate nucleotide variant was identified in the reviewed sources.
Sources
PS2 No confirmed de novo occurrence with verified maternity and paternity was identified. Details ▾Hide ▴
Still missing
- No de novo testing data were provided.
PS3 Published functional literature was identified, but the reviewed evidence did not provide sufficiently specific, validated variant-level functional results for p.Arg271Trp to support a PS3 assertion. Details ▾Hide ▴
Evidence considered
- AIP/PDE4A5 interaction biology reported
- missense variant interaction studies described at cohort level
- AIP structural-functional study reviewed
Still missing
- Direct variant-level functional assay results for p.Arg271Trp were not clearly established from the reviewed evidence.
Sources
PS4 This variant has been reported in multiple affected AIP-associated pituitary adenoma cohorts and families, including a large kindred with aggressive tumors, but the reviewed evidence did not provide a case-control enrichment analysis or another quantitative framework sufficient to apply PS4 under generic ACMG/AMP rules. Details ▾Hide ▴
Evidence considered
- R271W reported in familial isolated pituitary adenoma
- R271W reported in a Samoan kindred with aggressive pituitary tumors
- AIP mutation-positive young-onset pituitary adenoma cohorts reviewed
- ClinVar pathogenic/likely pathogenic submissions
Still missing
- No odds ratio
- prevalence comparison
- or other quantitative case-control assessment specific to this variant was identified.
Sources
PMID:17244780 ↗PMID:19684062 ↗PMID:21753072 ↗PMID:26186299 ↗clinvar ↗17244780196840622175307226186299
PM5 No evidence was identified showing a different pathogenic missense change at the same amino acid residue that would support PM5. Details ▾Hide ▴
Evidence considered
- ClinVar record reviewed
Still missing
- No alternate pathogenic missense substitution at codon 271 was established from the reviewed sources.
Sources
PM6 No assumed de novo occurrence without confirmed parentage was identified. Details ▾Hide ▴
Still missing
- No de novo data were provided.
PP1 Family-based observations were reported, but the reviewed evidence did not provide a segregation analysis sufficient for ACMG/AMP PP1. Unaffected carriers were also described, which is consistent with incomplete penetrance and limits straightforward segregation scoring. Details ▾Hide ▴
Evidence considered
- Affected and unaffected carriers described in published families
Still missing
- No formal meiosis-based segregation count or criterion-level segregation analysis was identified.
Sources
PP2 Available evidence was insufficient to conclude that AIP is a gene in which missense variation is a common disease mechanism and benign missense variation is rare enough to apply PP2. Details ▾Hide ▴
Evidence considered
- AIP missense variants discussed in cohort literature
Still missing
- No reviewed gene-level missense constraint or mechanism framework supporting PP2 was identified.
Sources
PMID:20506337 ↗20506337
PP4 No individual-level phenotype description was provided for this case, so the specificity of the clinical presentation for AIP-related disease could not be assessed. Details ▾Hide ▴
Still missing
- Case-specific phenotype information is needed.
BS2 No evidence was identified showing this variant in a sufficient number of well-phenotyped unaffected individuals for a disorder setting appropriate to BS2. Details ▾Hide ▴
Evidence considered
- Rare population presence only
- Incomplete penetrance described in AIP mutation carriers
Still missing
- Robust unaffected adult carrier data with phenotype context were not identified.
Sources
BS3 No well-established functional study showing normal protein function for p.Arg271Trp was identified. Details ▾Hide ▴
Evidence considered
- General AIP functional literature reviewed
Still missing
- Direct benign functional evidence for this specific missense variant was not established.
Sources
BS4 No evidence was identified showing lack of segregation with disease in informative affected family members. Details ▾Hide ▴
Evidence considered
- Published family observations reviewed
Still missing
- Formal non-segregation data were not identified.
Sources
BP1 Available evidence was insufficient to apply BP1. Although loss of function is an established AIP disease mechanism, missense variants have also been reported in affected individuals, so this criterion was not used. Details ▾Hide ▴
Evidence considered
- AIP loss-of-function mechanism supported
- missense variants reported in AIP literature
Still missing
- A gene-specific framework would be needed to justify BP1 for AIP.
Sources
BP2 No phase information with another pathogenic variant was identified to support BP2. Details ▾Hide ▴
Still missing
- No cis/trans observation with another pathogenic variant was provided.
BP5 No alternate molecular diagnosis explaining the phenotype was identified. Details ▾Hide ▴
Still missing
- Case-level alternate diagnosis information was not provided.
Not applicable · 7· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis is a missense variant, and the generic PVS1 framework indicates that it does not fall into the default null-variant categories eligible for PVS1. Although AIP loss of function is an established disease mechanism, c.811C>T (p.Arg271Trp) is not a nonsense, frameshift, or canonical splice-site variant. Details ▾Hide ▴
Rule
Generic ClinGen SVI PVS1 framework
Evidence considered
- AIP loss-of-function mechanism supported
- generic PVS1 scaffold excludes this missense variant
Sources
PM3 N/ANo evidence was identified that this variant was observed in trans with a pathogenic variant in a recessive disorder context. Details ▾Hide ▴
Evidence considered
- AIP familial pituitary adenoma literature reviewed
Sources
PM4 N/AThis is not a protein length-changing variant and does not involve an in-frame insertion, in-frame deletion, or stop-loss event. Details ▾Hide ▴
Evidence considered
- missense consequence p.Arg271Trp
PP5 N/AExternal pathogenic classifications were identified in ClinVar, but assertion-based criteria are not applied here in place of primary evidence review. Details ▾Hide ▴
BP3 N/AThis is not an in-frame insertion or deletion in a repetitive region. Details ▾Hide ▴
Evidence considered
- missense consequence p.Arg271Trp
BP6 N/ANo external benign classification was used as independent evidence, and assertion-based criteria were not applied in place of primary evidence review. Details ▾Hide ▴
BP7 N/AThis is a missense variant rather than a synonymous or noncoding variant, so BP7 does not apply. Details ▾Hide ▴
Identifiers
- Gene
- AIP
- Transcript
- NM_003977.4
- Coding (HGVS c.)
- NM_003977.4:c.811C>T
- Protein (HGVS p.)
- NP_003968.3:p.(Arg271Trp)
- GRCh38
- chr11:67490811 C>T
- GRCh37
- chr11:67258282 C>T
Gene diagram
Every interpreted variant in AIP, mapped onto the exon structure of NM_003977.4. Select a row to find it on the plot.
AIPNM_003977.4
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in AIP
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
5 / 1,612,452 alleles
AF 3.1e-06 · 0 homozygotes · FAF 7.9e-07
gnomAD v2.1
1 / 248,938 alleles
AF 4.02e-06 · 0 homozygotes
By genetic ancestry
gnomAD v4.1
AF 3.1e-06 · 5 / 1,612,452 alleles · 0 hom · FAF 7.9e-07
| South Asian1 / 91,052 | 1.1e-05 |
| European (non-Finnish)4 / 1,179,952 | 3.4e-06 |
0 alternate alleles recorded in 8 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, Ashkenazi Jewish, African/African American.
gnomAD v2.1
AF 4e-06 · 1 / 248,938 alleles · 0 hom
| South Asian1 / 30,600 | 3.3e-05 |
0 alternate alleles recorded in 7 other groups: African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Remaining individuals.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 3.10087e-06; MAF= 0.00031%, 5/1612452 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 1.09827e-05; MAF= 0.00110%, 1/91052 alleles, homozygotes = 0); grpmax FAF= 7.9e-07.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 4.01706e-06; MAF= 0.00040%, 1/248938 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 3.26797e-05; MAF= 0.00327%, 1/30600 alleles, homozygotes = 0).
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 SupportingMultiple computational results support a deleterious effect on the protein. REVEL is 0.785 and BayesDel is 0.292581, both favoring a damaging missense effect, while SpliceAI shows no predicted splice impact (max delta score 0.00). Overall, the in silico evidence supports pathogenicity at the protein level. Details ▾Hide ▴
Rule
Generic ACMG PP3 computational support
Evidence considered
- REVEL 0.785
- BayesDel 0.292581
- SpliceAI max delta 0.00
Sources
BP4 Available computational evidence does not support a benign interpretation. REVEL is 0.785 and BayesDel is 0.292581, both favoring a damaging missense effect; although SpliceAI predicts no splice disruption (max delta score 0.00), the overall in silico evidence does not support BP4. Details ▾Hide ▴
Evidence considered
- REVEL 0.785
- BayesDel 0.292581
- SpliceAI max delta 0.00
Sources
BP7 N/AThis is a missense variant rather than a synonymous or noncoding variant, so BP7 does not apply. Details ▾Hide ▴
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.785. BayesDel score = 0.292581.
0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
5 / 1,612,452 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Captured SpliceAI source record
Open source ↗
ClinVar
Captured ClinVar source record
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
OncoKB
Captured OncoKB source record
Open source ↗
All source links
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/41210/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/11-67258282-C-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr11-67490811-C-T?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_003977.4%3Ac.811C…
- OncoKB ↗www.oncokb.org/gene/AIP/R271W
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=AIP+c.811C%3ET
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 3.10087e-06; MAF= 0.00031%, 5/1612452 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 1.09827e-05; MAF= 0.00110%, 1/91052 alleles, homozygotes = 0); grpmax FAF= 7.9e-07.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 4.01706e-06; MAF= 0.00040%, 1/248938 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 3.26797e-05; MAF= 0.00327%, 1/30600 alleles, homozygotes = 0).
ClinVar
This variant has been reported in ClinVar as Pathogenic (4 clinical laboratories) and as Likely pathogenic (1 clinical laboratory).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.785. BayesDel score = 0.292581.
Functional
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. AIP, an aryl hydrocarbon receptor-interacting protein, is infrequently altered in cancer.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.